In this excellent review from the EFI's HAD Bridging Project, the Haloalkanoic Acid Dehalogenase (HAD) superfamily is showcased in a retrospective analysis of enzyme promiscuity. Topics include: how promiscuity is assessed via high throughput screening, the physiological benefits of promiscuity, and the structural basis of promiscuity, with an emphasis on domain insertions. Complimentary to the sequence-oriented approaches employed elsewhere in the EFI, the HAD superfamily provides an ideal test set to explore the structure-function relationship.
Catalytic promiscuity and substrate ambiguity are keys to evolvability, which in turn is pivotal to the successful acquisition of novel biological functions. Action on multiple substrates (substrate ambiguity) can be harnessed for performance of functions in the cell that supersede catalysis of a single metabolite. These functions include proofreading, scavenging of nutrients, removal of anti-metabolites, balancing of metabolite pools, and establishing system redundancy. In this review we present examples of enzymes that perform these cellular roles by leveraging substrate ambiguity and then present the structural features that support both specificity and ambiguity. We focus on the phosphatases of the haloalkanoate dehalogenase superfamily and the thioesterases of the hotdog-fold superfamily.
This research was originally published in Journal of Biological Chemistry. Pandya C, Farelli JD, Dunaway-Mariano D, Allen KN. Enzyme Promiscuity: Engine of Evolutionary Innovation. J Biol Chem. 2014; jbc.R114.572990. © the American Society for Biochemistry and Molecular Biology.